ASA404, a vascular disrupting agent, as an experimental treatment approach for brain tumors.
ASA404, a vascular disrupting agent, as an experimental treatment approach for brain tumors.
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DOI：
10.3892/ol.2017.6832
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发表时间：
2017-11
期刊：
影响因子：
2.9
通讯作者：
Mittelbronn M
中科院分区：
文献类型：
--
作者：
Bähr O;Gross S;Harter PN;Kirches E;Mawrin C;Steinbach JP;Mittelbronn M
恶性脑肿瘤，包括神经胶质瘤、脑转移瘤和间变性脑膜瘤，与不良预后相关，并且代表未满足的医疗需求。ASA 404（DMXAA）是一种血管阻断剂，在几种临床前肿瘤模型和早期临床试验中显示出有希望的结果。然而，两项针对非小细胞肺癌的III期试验报告的结果不足。本研究的目的是确定ASA 404对脑肿瘤的影响。使用恶性胶质瘤（U-87、LN-229、U-251、LN-308和Tu-2449）、脑转移瘤（HT-29）和恶性脑膜瘤（IOMM-Lee）的皮下和原位模型，在体外和体内评价ASA 404的作用。使用常规和免疫组织化学染色技术[苏木精和伊红、MIB-1抗体/增殖标记蛋白Ki-67、切割的半胱天冬酶-8、干扰素基因刺激因子（STING）、离子化钙结合衔接分子1]分析ASA 404对肿瘤组织的急性作用。此外，测量了皮下肿瘤的大小，并分析了接受ASA 404治疗的颅内肿瘤动物的无瘤生存率。ASA 404在体外表现出低毒性，但在单剂量ASA 404（25 mg/kg）后24 h对皮下肿瘤表现出强烈的作用。ASA 404可诱导皮下胶质瘤模型中肿瘤的坏死、膨胀，并抑制肿瘤的增殖和生长。然而，ASA 404未能在所检查的任何颅内肿瘤模型中表现出相当的效果，并且没有导致生存期延长。STING的表达，ASA 404的分子靶点，巨噬细胞的浸润，介导ASA 404活性的细胞，在皮下和颅内肿瘤之间没有差异。总之，ASA 404在皮下肿瘤模型中表现出明确的疗效，但在原位脑肿瘤模型中没有相关活性。STING的表达和巨噬细胞浸润未被确定参与肿瘤模型中观察到的差异活性。可能是阿萨-404对大脑的低渗透性阻止了足够的浓度到达肿瘤，从而在体内表现出急性效应。
Malignant brain tumors, including gliomas, brain metastases and anaplastic meningiomas, are associated with poor prognosis, and represent an unmet medical need. ASA404 (DMXAA), a vascular disrupting agent, has demonstrated promising results in several preclinical tumor models and early phase clinical trials. However, two phase III trials in non-small cell lung cancer reported insufficient results. The aim of the present study was to determine the effects of ASA404 on brain tumors. The effects of ASA404 were evaluated in vitro and in vivo using subcutaneous, and orthotopical models for malignant glioma (U-87, LN-229, U-251, LN-308 and Tu-2449), brain metastasis (HT-29) and malignant meningioma (IOMM-Lee). The acute effects of ASA404 on tumor tissue were analyzed using conventional and immunohistochemical staining techniques [hematoxylin and eosin, MIB-1 antibody/proliferation maker protein Ki-67, cleaved caspase-8, stimulator of interferon genes (STING), ionized calcium-binding adapter molecule 1]. Furthermore, the sizes of subcutaneous tumors were measured and the symptom-free survival rates of animals with intracranial tumors receiving ASA404 treatment were analyzed. ASA404 demonstrated low toxicity in vitro, but exhibited strong effects on subcutaneous tumors 24 h following a single dose of ASA404 (25 mg/kg). ASA404 induced necrosis, hemorrhages and inhibited the proliferation, and growth of tumors in the subcutaneous glioma models. However, ASA404 failed to demonstrate comparable effects in any of the intracranial tumor models examined and did not result in a prolongation of survival. Expression of STING, the molecular target of ASA404, and infiltration of macrophages, the cells mediating ASA404 activity, did not differ between subcutaneous and intracranial tumors. In conclusion, ASA404 demonstrates clear efficacy in subcutaneous tumor models, but has no relevant activity in orthotopic brain tumor models. The expression of STING and infiltration with macrophages were not determined to be involved in the differential activity observed among tumor models. It is possible that the low penetration of ASA-404 into the brain prevents concentrations sufficient enough reaching the tumor in order to exhibit acute effects in vivo.
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影响因子：
64.5
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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